Activation and stabilization of aldimines by an ortho-trifluoromethyl substituent in direct vinylogous Mannich-type reactions

Article abstract of DOI:10.1016/j.tetlet.2004.04.165

Lewis acid catalyzed direct vinylogous Mannich-type reaction with a weak nucleophile dienol, generated in situ by ring-opening and rearrangement of vinyloxiranes, could be demonstrated in excellent yields under mild conditions using benzylidene(4-methoxy-2-trifluoromethyl)aniline (MTMA) as an electrophile. The o-trifluoromethyl substituent can stabilize imines by a steric effect and activate by an electron-withdrawing effect. It proved to be an easily deprotectable protecting group for direct Mannich-type reactions.

Full text of DOI:10.1016/j.tetlet.2004.04.165

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5131–5133
Activation and stabilization of aldimines by an
ortho-trifluoromethyl substituent in direct vinylogous
Mannich-type reactions
Mark Lautens,* Eiji Tayama and Duy Nguyen
Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario, Canada M5S 3H6
Received 29 October 2003; revised 22 April 2004; accepted 28 April 2004
Abstract—Lewis acid catalyzed direct vinylogous Mannich-type reaction with a weak nucleophile dienol, generated in situ by ring-
opening and rearrangement of vinyloxiranes, could be demonstrated in excellent yields under mild conditions using benzylidene(4-
methoxy-2-trifluoromethyl)aniline (MTMA) as an electrophile. The o-trifluoromethyl substituent can stabilize imines by a steric
effect and activate by an electron-withdrawing effect. It proved to be an easily deprotectable protecting group for direct Mannich-
type reactions.
Ó 2004 Elsevier Ltd. All rights reserved.
The Mannich reaction is an important synthetic proce-
dure to prepare nitrogen-containing compounds, which
has been applied to the synthesis of heterocyclic building
blocks, biologically active compounds, and natural
products. Several kinds of nucleophiles have been used
for nucleophilic addition at the imino carbon, for
example, enolates, malonates, and silyl or tin enol-
ethers.1 In every cases, the imine was less reactive as an
electrophile than the corresponding aldehyde and many
imines are unstable under typical reaction conditions. In
the Lewis acid catalyzed Mannich-type reaction, lower
temperature and/or active nucleophiles were required to
prevent acid catalyzed decomposition of imines.2 Re-
cently Lewis acid catalyzed Mannich-type reactions
could be performed under mild conditions but the
reaction with a weak nucleophile, such as an enol, led to
formation of side products.3 We report, activated and
stabilized aldimines4 derived from 4-methoxy-2-trifluo-
romethylaniline (MTMA)5 and aromatic aldehydes re-
act with a weak nucleophilic dienol, generated from a
vinyloxirane. This is a new application of direct vinyl-
ogous Mannich-type reactions produced via Lewis acid
catalyzed ring opening and rearrangement of vinyloxi-
ranes.6
In the direct vinylogous Mannich-type reaction,
2-methyl-2-vinyloxirane was converted to the corre-
sponding b,c-unsaturated aldehyde by Lewis acid cata-
lyzed ring opening and rearrangement (Scheme 1).7 This
aldehyde is easily isomerized to the dienol under the
reaction conditions where it behaves as a nucleophile in
a direct vinylogous Mannich-type reaction. Represen-
tative results are listed in Table 1. Phenyl and tolyl
aldimine 1a, 1b gave the corresponding d-amino-a,b-
unsaturated aldehydes 2a, 2b as Mannich adducts in
quantative yields (entry 1 and 2) under mild conditions
(THF, 0 °C) in the presence of a catalytic amount
BF3ÆOEt2 (20 mol %). An o-trifluoromethyl group on an
aniline ring enhanced the stability of the imines toward
hydrolysis and also activated the imino carbon to
nucleophilic addition. Thus, reactions occurred without
H
ring-opening
1,2-shift
Lewis acid
(LA)
O
O
LA
CHO
LA
equilibrium
OH
β,γ-unsaturated
aldehyde
(electrophile)
dienol
(nucleophile)
Keywords: Mannich-type; Vinylogous; Vinyloxirane; Rearrangement.
* Corresponding author. Tel./fax: +1-416-978-6083; e-mail:
mlautens@chem.utoronto.ca
Scheme 1. Lewis acid catalyzed rearrangement of vinyloxirane to the
corresponding b,c-unsaturated aldehyde.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.165

5132
M. Lautens et al. / Tetrahedron Letters 45 (2004) 5131–5133
Table 1. BF3ÆOEt2 catalyzed rearrangement of vinyloxirane and direct
vinylogous Mannich-type reactions
Ar
Ar
HN
Ph
HN
Ph
NaBH4
MeOH
0 ºC to rt
CHO
OH
F3C
HN
OMe
CHO
F3C
N
OMe
20 mol% BF3·OEt2
2a
5
O (1.5 equiv)
Boc
(Boc)2O
K2CO3
THF-H2O
HN
Ph
THF, 0 ºC, time
R
R
H
N2H4·H2O
CAN
OH
CH3CN-H2O
Et2O
rt
1a-h
2a-h
0 ºC
rt
6
83% (from 2a)
Entry
R
Time (h)
Yielda (%)
(Ar = 4-methoxy-2-trifluoromethylphenyl)
1
2
Ph
4-Me–Ph
a
b
c
d
e
f
399
399
390
390
396
393
5
Scheme 3. Deprotection by oxidative conditions.
34-Cl–Ph
4
5
6
7
8
2-Cl–Ph
2-Br–Ph
2-I-Ph
and re-protection with (Boc)2O without purification
gave the corresponding Boc-protected amino allyl
alcohol 6 in 83% yield (Scheme 3).
4-MeO–Ph
t-Bu
g
h
73
3
2
0
a Isolated yield.
A typical experimental procedure for the direct vinylo-
gous Mannich-type reactions is as follows: To a solution
of aldimine 1a (249 mg, 0.892 mmol) and 2-methyl-2-
vinyloxirane (132 lL, 1.34 mmol) in THF (1.8 mL) was
added a 1.0 M solution of BF3ÆOEt2 in toluene (0.18 mL,
0.18 mmol) at 0 °C. After stirring for 3h at the same
temperature, the resulting mixture was quenched with
saturated NaHCO3. Extractive workup and purification
by column chromatography on silica gel (hexane/
EtOAc ¼ 7:1 to 4:1 as eluent) gave the corresponding d-
amino-a,b-unsaturated aldehyde 2a as a colorless vis-
cous oil (319 mg, 0.879 mmol, 99% yield).9
side reactions and o-chloro, p-chloro, o-bromo, and
o-iodophenyl aldimine 1c–f also gave the Mannich ad-
duct in over 90% yields under the same conditions (entry
3–6). p-Methoxyphenyl aldimine 1g gave the adduct in
moderate yield (entry 7, 2g, 73%) however tert-butyl
aldimine 1h gave low yield due to steric effects (entry 8,
2h, 30% yield).
We investigated the reactivity of other vinyloxiranes to
determine the scope of the reaction (Scheme 2). 2-Ethyl-
2-vinyloxirane also generated the corresponding dienal
by BF3ÆOEt2 catalyzed rearrangement. This dienal
seemed to be less reactive and the Mannich addition to
1a only proceeded at room temperature to give a d-
amino-a,b-conjugated aldehyde 3 in 76% yield. By the
same approach, a,b-conjugated ketone 4 also could be
obtained. 2,3-Dimethyl-2-vinyloxirane rearranged to the
diketal and reacted with aldimine 1a in 80% yield.
Higher temperature (50 °C) was required due to less
nucleophilicity of the diketal than the dienal. In this
case, Sc(OTf)3 gave good result as a Lewis acid catalyst.
Acknowledgements
We would like to thank Merck Frosst Canada, NSERC
and the University of Toronto for support of this
research program.
References and notes
An added advantage of the MTMA group is its ease of
deprotection under oxidative conditions after reduction
of the amino aldehyde 2a to an amino alcohols 5 with
NaBH4. Oxidization of 5 with CAN (ceric ammonium
nitrate) in CH3CN–H2O and treatment with N2H4ÆH2O8
1. Kleinman, E. F. In Comprehensive Organic Synthesis;
Trost, B. M. , Ed.; Pergamon: Oxford, 1991; Vol. 2,
Chapter 4.1, p 893.
2. Recent examples of Lewis acid catalyzed Mannich-type
reactions: (a) Ueno, M.; Ishitani, H.; Kobayashi, S. Org.
Lett. 2002, 4, 3395; (b) Kobayashi, S.; Ishitani, H.;
Yamashita, Y.; Ueno, M.; Shimizu, H. Tetrahedron 2001,
57, 861; (c) Manabe, K.; Oyamada, H.; Sugita, K.;
Kobayashi, S. J. Org. Chem. 1999, 64, 8054; (d) Koba-
yashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.; Kim, H.-S.;
Wataya, Y. J. Org. Chem. 1999, 64, 6833; (e) Akiyama, T.;
Takaya, J.; Kagoshima, H. Chem. Lett. 1999, 947.
3. An example of Mannich-type reactions with an enol as a
nucleophile: Wang, M.; Yang, X.-F.; Li, C.-J. Eur. J. Org.
Chem. 2003, 998.
4. Prepared by condensation of the corresponding aldehyde
and 4-methoxy-3-trifluoromethylaniline (toluene, reflux,
Dean-Stark trap).
5. Prepared from 3-trifluoromethylphenol in ca. 30–40% yield
(three steps): (i) Nitration (conc HNO3, CH2Cl2, 0 °C); (ii)
Methylation (MeI, K2CO3, acetone, reflux); (iii) Reduction
(C, FeCl3, N2H4ÆH2O, MeOH, reflux).
20 mol% BF3·OEt2
Ar
Ar
HN
O
N
(1.5 equiv)
Et
CHO
Ph
THF
0 ºC to rt
1 h
Ph
H
Et
1a
3
76%
10 mol% Sc(OTf)3
(2.0 equiv)
Ar
HN
Ph
O
O
1a
CH3
THF
0 to 50 ºC
1 h
4
81%
(Ar = 4-methoxy-2-trifluoromethylphenyl)
Scheme 2. Reactivity of other types of vinyloxiranes.

M. Lautens et al. / Tetrahedron Letters 45 (2004) 5131–5133
5133
6. (a) Lautens, M.; Tayama, E.; Nguyen, D. Org. Lett. 2004,
6, 345; (b) Lautens, M.; Maddess, M. L.; Sauer, E. L. O.;
Ouellet, S. G. Org. Lett. 2002, 4, 83; (c) Lautens, M.; Ouel-
let, S. G.; Raeppel, S. Angew. Chem., Int. Ed. 2000, 39, 4079.
7. Examples of Lewis acid catalyzed rearrangement of viny-
loxiranes: (a) Jung, M. E.; Anderson, K. L. Tetrahedron
Lett. 1997, 38, 2605; (b) Jung, M. E.; D’Amico, D. C. J.
Am. Chem. Soc. 1995, 117, 7379; (c) Wipf, P.; Xu, W.
J. Org. Chem. 1993, 58, 825.
8.39 (1H, s, CH@N), 7.93–7.90 (2H, m, Ar–H), 7.50–7.46
(3H, m, Ar–H), 7.22 (1H, s, Ar–H), 7.07 (2H, d, J ¼ 1:2 Hz,
Ar–H), 3.86 (3H, s, OMe); 13C NMR (75 MHz, CDCl3)
d
160.0, 157.3, 143.4, 136.1, 131.5, 129.0, 128.7,
125.5, 124.9, 124.5, 121.9, 120.1, 117.9, 112.0 (q, J ¼ 5 Hz),
55.7; IR (film) 3058, 3003, 2942, 2833, 1630, 1494, 1429,
; HRMS
1314, 1229, 1127, 1042, 872, 817, 773 cmÀ1
(EI) calcd for C15H12F3NO (Mþ): 279.0871. Found:
279.0876.
N-(4-Methoxy-2-trifluoromethylphenyl)-5-amino-2-methyl-
8. Ohkura, H.; Handa, M.; Katagiri, T.; Uneyama, K. J. Org.
Chem. 2002, 67, 2692.
9. Selected spectroscopic data are as follows: 2-Trifluoro-
1
5-phenylpent-2-en-1-nal (2a): yellow viscous oil; H NMR
(300 MHz, CDCl3) d 9.39 (1H, s, CHO), 7.38–7.24 (5H, m,
Ar–H), 7.01 (1H, d, J ¼ 2:7 Hz, Ar–H), 6.79 (1H, dd,
J ¼ 8:7, 2.7 Hz, Ar–H), 6.49 (1H, d, J ¼ 7:2 Hz, 3-CH),
6.44 (1H, d, J ¼ 8:7 Hz, Ar–H), 4.58 (1H, td, J ¼ 6:3,
6.3 Hz, 5-CH), 4.45 (1H, br, NH), 3.70 (3H, s, OMe), 2.95–
2.79 (2H, m, 4-CH2), 1.74 (3H, s, 2-CH3); 13C NMR
(75 MHz, CDCl3) d 194.6, 151.0, 148.3, 142.0, 141.8, 138.4,
129.0, 127.7, 126.6, 126.1, 123.0, 119.0, 115.0, 114.9, 114.5,
112.1 (q, J ¼ 6 Hz), 57.3, 55.8, 38.1, 9.3; IR (film) 3447,
3058, 2935, 2833, 2710, 1684, 1514, 1426, 1324, 1218, 1100,
1042, 885, 811 cmÀ1; HRMS (ESI) calcd for C20H21F3NO2
[(M+H)þ]: 364.1518. Found: 364.1526.
1
methyl-4-methoxyaniline: yellow oil; H NMR (300 MHz,
CDCl3) d 6.97 (1H, d, J ¼ 2:7 Hz, 3-H), 6.91 (1H, dd,
J ¼ 8:7, 2.7 Hz, 5-H), 6.70 (1H, d, J ¼ 8:7 Hz, 6-H), 3.88
(2H, br, NH2), 3.76 (3H, s, OMe); 13C NMR (75 MHz,
CDCl3) d 151.8, 138.2 (d, J ¼ 2 Hz), 126.5, 122.8, 119.7,
118.9, 111.1 (q, J ¼ 5 Hz), 55.8; IR (film) 3481, 3386, 3235,
3003, 2942, 2833, 1636, 1623, 1511, 1429, 1290, 1229, 1106,
1038, 892, 821, 733 cmÀ1
; HRMS (ESI) calcd for
C8H9F3NO [(M+H)þ]: 192.0630. Found: 192.0630.
Benzylidene(4-methoxy-2-trifluoromethyl)aniline (1a): yel-
1
low crystal, mp ¼ 53–54 °C; H NMR (300 MHz, CDCl3) d